dissolution rate enhancing techniques
TRANSCRIPT
VIJAYA INSTITUTE OF PHARMACEUTICAL SCIENCES FOR WOMEN
ENIKEPADU, VIJAYAWADA.
Mr. S.VENKATESWARA RAO,
Assoc. Professor,
Department of Pharmaceutics
DISSOLUTION RATE ENHANCING TECHNIQUES
DISSOLUTION: Dissolution is a mass transfer process from solid
phase to liquid phase
It is rate limiting step in absorption of drugs
Absorption of a drug and its bioavailability mainly depends on
solubility and dissolution rate
DISSOLUTION RATE : Dissolution rate is the amount of solute
enter into dissolution medium pre unit time under standard conditions
of temperature, pH, Composition of dissolution medium, effective
surface area
Dissolution rate can be calculated using equation
dc/dt=K(Cs-Cb)Noyes And Whitney Equation:
Modified Noyes and whitney equation:
dc/dt = DAKw/o(Cs-Cb)
Vh
DISSOLUTION RATE ENHANCING TECHNIQUES
I. PHYSISICAL MODIFICATION
(A). PARTICLE SIZE REDUCTION
(B). SOLID DISPERSION
(C). COMPLEXATION
II . CHEMICAL MODIFICATION
(A). pH ADJUSTMENT
(B). DRUG DERIVITISATION
(C). SALT FORMATION
III. MISCELLANEOUS
(A). SOLVENT DEPOSITION
(B). HYDROTROPHY
(1) Micronization:
Micronization increases the dissolution rate of the drugs
by increasing the surface area
This process involves reducing the size of the solid drug
particles to 1 to 10 microns commonly by spray drying or
by use of attrition methods (fluid energy or jet mill).
Ex; sulpha drugs,steroids, griseofulvin
I. PHYSICAL MODIFICATION
(A) PARTICLE SIZE REDUCTION
Colloid mill
*dc/dt ∝A
This is practically true in nonhydrophyllic drugs likegriseofulvin, Chloramphenicol, Steroids, Sulpha drugs.
This is practically false in hydrophobic drugs like
Asprin, Phenacitin, Phenobarbital.
Reasons:
1) Absorb air on hydrophobic surface
2) Due to their high surface free energy
3) Impart surface charges to the particles
An average particle size ranging between 200 and 600 nm.
This technology is applied for poorly soluble drugs that are
insoluble in both water and oils.
Size reduction results surface area dissolution rate and
bio availability.
Ex: Amphotericin-B
(2) Nanonization:
Sub micronised particlesMicropaticles(Nano particles)
Patented engineering process based on the principles
of ; .
(a) Pearl milling
(b) High pressure homogenization
(c) Co-micronization
(d) Supercritical fluid process
(e) Spray freezing into liquid
(f) Rapid expansion from super critical to aqueous
solution
Patented engineering techniques under nanonization:
(a) Co-micronization :
drug Co micronization reduced drug particle size
energy
vanderwall
leads
Agglomeration ( effective surface area)
Microcrystalline cellulose can be used to reduce vanderwall
interaction,electrostatic attraction b/w particles
interaction,electrostatic attraction
b/w particles
(b)Supercritical fluid process:
This is the novel nano-sizing and solubilization
technology and it’s application has increased in
recent years is particle size reduction via
supercritical fluid (SCF)processes
Commonly used
supercritical solvents
include Co2, nitrous oxide,
ethylene, propylene,propane,
n-pentane,C2H5OH,NH3, and
H20.
(B). DRUG DISPERSION IN CARRIERS:
(1).Solid dispersions:
In this technique, a poorly soluble drug is dispersed in a
highly soluble solid hydrophilic matrix, by that enhances
the dissolution of the drug.
Solid dispersion techniques yields eutectic or solid
solution products.
Eg: A solid dispersion of carbamazepine in polyethylene
glycol 4000 (PEG-4000) increased the rate and extent of
dissolution of carbamazepine.
(a) SOLVENT EVAPORATION METHOD:
DRUG DISPERSIONS are mainly prepared by 3 methods
Drug +carrier SolutionCooling
Super saturation
milled
Particle size is reduced
(b) HOT MELT METHOD :
Ex; ß-Carotene,
Meloxicam, Naproxen,
Nimesulide
Ex; Sulphathiazole drug,urea as carrier
melting
Hot melt extrusion method is most preferable for the preparation
of Solid solutions. Eg: The solubility of the drug itraconazole has
increased by this technique by using HPMC as carrier.
(c) HOT MELT EXTRUSION METHOD:
Eutectic mixtures are prepared by rapid solidification of the fused
liquid of two components
(2) EUTECTIC MIXTURES:
Which show complete liquid miscibility.
When eutectic mixtures composed of poorly soluble drugs is exposed
to water (or) GI Fluid
The carrier (urea) gets released into the aqueous media leaving the
drug in fine crystalline form
Eg: Paracetamol-urea, Griseofulvin-urea.
(C). COMPLEXATION:
Inclusion complexes are formed by the insertion of the nonpolar
molecule of one molecule (known as guest) into the cavity of another
molecule or group of molecules (known as host).
Eg: Rofecoxib54, Piroxicam55 and Carvedilol56 can be improved by
using cyclodextrins
Different types of complexing agents are used for different types of
complexation techniques,
(D). MODIFICATION OF THE CRYSTAL HABIT:
Changing the crystal habit means changing one form to another form
(i.e; crystalline form to amorphous)
Amorphous form shows more solubility than meta stable
polymorphs, anhydrates are more soluble than hydrates and solvates
are more soluble than non-solvates.
S.No Type Example
1. Coordination Hexamine(III)cobalt chloride
2. Chelates EDTA,EGTA
3. Metal-olefin Ferrocene
4. Molecular complexes Polymers
Amorphous > Metastable polymorphs > Stable polymorphs
Polymeric form of riboflavin 3 is 20times more D.R than
riboflavin 1
Cortisone acetate, Phenobarbital, Novobiocine amorphous form
have more dissolution rate
Order for dissolution of different forms of drug is
For Example Chloramphenicol-B more soluble than A & C
(E). SOLUBILIZATION BY SURFACTANTS:
They enhance dissolution rate primarily by promoting wetting and
penetration of dissolution fluid into the solid drug particles.
Eg: Solubility enhancement of antimicrobial drug enrofloxacin using a
series of co-solvents and surfactants. Aqueous solubility of
enrofloxacin could be increased up to 26 times.
Microemulsions are potential drug delivery systems for poorly
water-soluble drugs
because to their ability to solubilize the drugs in the oil phase,
thus increasing their dissolution rate and these are called as
micro because it consists of <0.1 micron droplet diameter.
Mechanism of action of surfactants
II . CHEMICAL MODIFICATION
(A). pH ADJUSTEMENT:
The absorption of drug is largely dependent
upon diffusion, which varies with pH of the
individual regions within the gastrointestinal
tract, the pKa of the drug and permeability
also depends upon pH effects upon drug
ionization.
By applying a pH change, poorly water soluble
drug molecules that can be protonated (base) or
deprotonated (acid) may practically dissolved in
water.
The principle of in situ salt formation has been
used to enhance dissolution rate of drugs like
Asprin, Pencillin from buffered alkaline tablets
(B). SALT FORMATION:
Salt formation of poorly soluble drugs (weak acids and bases) has
been used for to enhance solubility,
Weakly acidic drugs , a strong base salt is prepared such as Na , K
salts of Barbiturates
Weakly basic drugs a strong acid salt is prepared like Hcl ,
Sulphate
Eg: Alkali metal salt of acidic drugs like penicillin & strong acid salt
of basic drugs like atropine more water soluble than parent drug
The solubility of salt form of the drug mainly depends on
counter ion size.
Ex: Novobiocin, Stearates
(C). DERIVATIZATION:
Derivatization is a technique used by which transforms achemical compound into a product (the reaction's derivate) ofsimilar chemical structure, called a derivative.
Phosphate group is most commonly used group to increase
aqueous solubility
Ex: Clindamycin-Hcl (is soluble)
Clindamycin2 phosphate(is more soluble)
• Sulphate group improve solubility and improve dissolution rate
of prednisolone.
• Prodrugs as its Na salt improve the solubility of parent
Glucocorticoid.
The solvent deposition system is a solid preparation in which
a drug is deposited from a solvent on the surface of a matrix.
This step is usually done by simple evaporation of the solvent
used for distribution of the drug onto the matrix
Eg: The poorly aqueous soluble drug such as Nifedipine is
formulated as solid dispersion and carrier is microcrystalline
cellulose
(A).SOLVENT DEPOSITION
III OTHER METHODS
Method of preparation of
Solvent deposition:
Solvent deposition system prepared with different drugs and
carrier:
(B). HYDROTROPHY:
Hydrotrophy is a solubilization process, whereby addition of a
large amount of second solute that is the hydrotropic agent
increases the aqueous solubility of first solute.
Hydrotropic agents are ionic organic salts, consists of alkali
metal salts of various organic acids.
The mechanism by which it enhances solubility is more closely
related to complexation involving a weak interaction between
the hydrotropic agents like sodium benzoate, sodium acetate,
sodium alginate, urea, and the poorly soluble drugs.
Hydrotropic solubilization of various poorly water-soluble drugs:
S.No Drug Hydrotropic Agent
1. Progesterone, Diazepam and
Griseofulvin
Nicotinamide, Isonicotinamide
2. Paracetamol Sodium salicylate, Nicotinamide
3. Rofecoxib, celecoxib, melocoxib Nicotinamide, Sodium benzoate,
4. Riboflavin Nicotinamide
5. Ibuprofen Sodium salt of Ibuprofen
6. Nifedipine Urea, Methyl urea, Ehhyl urea, Butyl
urea, , N, N-dimethyl nicotinamide
7. Carbamazepine Sodium salicylate, Sodium benzoate
8. Riboflavin ProcaineHCl, Resorcinol, Pyrogallol
9. Diazepam, Oxazepam, Nitrazepam,Clonazepam
Sodium salicylate
(C).USE OF SOLUBLE PRODRUG:
This is the method of enhancing solubility by improving the physico-
chemical properties of the drug by boi-reversible chemical alteration.
It involves the incorporation of polar or ionizable moiety into the
parent compound to improve the aqueous solubility.
Example : Prodrug has been successfully used to improve water
solubility of corticosteroids, benzodiazepines.
(D). SELECTIVE ADSORPTION ON INSOLUBLE CARRIERS:
The drug particles are deposits on the bentonite and the rapid
release of the drug from the surface of the clays occurs due to
The weak physical bonding between the adsorbate and
adsorbent
Hydration and swelling of the clay in the aqueous media.
Non polar molecules and weak electrolytes have poor water
solubility
It can be improved by improved by changing the polarity of the
molecule and this can be achieved by addition of another
solvent.
Mainly cosolvency works by reducing the interfacial tension or
surface tension between the aqueous solution and hydrophobic
solute.
Examples of co-solvents are PEG-300, propylene glycol,ethanol.
(E). COSOLVENCY:
Ultrasound energy to modify the nucleation of a crystallization
process is known as sonocrystallization
The energy of ultrasound fashions consecutive compression and
expansion.
In sonocrystallization ultrasound used in the range of 20K Hz-5M
Hz.
(F). SONOCRYSTALLIZATION:
PROCESS OF SONOCRYSTALLIZATION
(G). SOLUBILIZING AGENTS:
Solubility of poorly soluble drugs can be enhanced by using various
solubilizing agents
Eg: PEG-400 is improving the solubility of hydrochlorthiazide85.
Solubilizer Solubilizate
Polyoxyethylene
monoalkylether
Essential oils
Sucrose monoesters Vitamin-A,D,E
Fatty acid ester 21-acetoxy pregnenolone,
Barbitol,Caffine
Polyoxyethylene sorbitan Acetamenaphtone
CONCLUSION
By this I conclude that, Dissolution of drug is the rate
determining step for oral absorption of the poorly water
soluble drugs and also the basic requirement for the
formulation and development of different dosage form of
different drugs.
Because of dissolution problem of many drugs, the
bioavailability of them gets affected and hence dissolution
enhancement becomes necessary. It is now possible that
to increase the dissolution of poorly soluble drugs with the
help of various techniques as mentioned above.
REFERENCES:
(1) Biopharmaceutics and Pharmacokinetics by D.M Bramankar Pg
No.349
(2) International journal of Pharmaceutical sciences and research by
Yogesh S.Thorat Solubility enhancement Techniques; September
2011
(3) The Theory and Practice of Industrial pharmacy by Lachmann Pg
no 463
(4). Journal of Advanced Pharmacy Education & Research;
Enhancement of solubilization and bioavailability of poorly soluble
drugs by Neha Gulati, V. K. Sharma; 20th January-2012.